Ever since the official debut of the epothilones in 1996 [e.g. EpoA (Compound 1) and EpoB (Compound 2), [Höfle et al., Angew. Chem. 1996, 108, 1671-1673; Angew. Chem. Int. Ed. 1996, 35, 1567-1569.] synthetic chemists have been enamored with their structures,
both from the synthesis and modification points of view. [a) Altmann, Org. Biomol. Chem. 2004, 2, 2137-2152; b) Watkins et al., Curr. Pharm. Design 2005, 11, 1615-1653; c) Nicolaou et al., Chem. Commun. 2001, 1523-1535; d) Nicolaou et al., Pure Appl. Chem. 1999, 71, 989-997; e) Harris et al., J. Org. Chem. 1999, 64, 8434-8456; f) Nicolaou et al., Angew. Chem. 1998, 110, 2120-2153; Angew. Chem. Int. Ed. 1998, 37, 2014-2045] This rather intense and persistent interest is neither surprising nor without merit, for these naturally occurring substances have proven themselves challenging targets for synthesis, powerful tools in biology, and worthydrug candidates currently in clinical trials [a) Okuno et al., J. Clin. Oncol. 2005, 23, 3069-3073; b) Altmann, Curr. Pharm. Design 2005, 11, 1595-1613; c) Rivkin et al., Angew. Chem. 2005, 117, 2898-2910; Angew. Chem. Int. Ed. 2005, 44, 2838-2850; d) Kolman, Curr. Opin. Invest. Drugs 2004, 5, 1292-1297; e) Kolman, Curr. Opin. Invest. Drugs 2004, 5, 657-667; f) Galmarini et al., iDrugs 2003, 6, 1182-1187; g) Biswas et al., J. Am. Chem. Soc. 2002, 124, 9825-9832] as anticancer agents.
Structure activity relationship (SAR) studies within the epothilone class of the present inventors and co-workers [Nicolaou et al., Chem. Commun. 2001, 1523-1535; Nicolaou et al., Pure Appl. Chem. 1999, 71, 989-997; Nicolaou et al., Angew. Chem. 1998, 110, 2120-2153; Angew. Chem. Int. Ed. 1998, 37, 2014-2045; a) Buey et al., Chem. Biol. 2004, 11, 225-236; Nicolaou et al., Angew. Chem. 2003, 115, 3639-3644; Angew. Chem., Int. Ed. 2003, 42, 3515-3520; Nicolaou et al., Tetrahedron 2002, 58, 6413-6432; Nicolaou et al., J. Am. Chem. Soc. 2001, 123, 9313-9323; Nicolaou et al., Chem. Biol. 2000, 7, 593-599] defined a narrow range of structural motifs that, when present, endow the epothilone molecule with biological activity and resulted in several potent epothilones such as the methylthio EpoB analogue Compound 3 [Nicolaou et al., Tetrahedron 2002, 58, 6413-6432] and Compound 4 [Nicolaou et al.,
Angew. Chem. 2003, 115, 3639-3644; Angew. Chem., Int. Ed. 2003, 42, 3515-3520]. This model was more or less confirmed by a recent electron crystallographic and nuclear-magnetic resonance-based conformational analysis [Nettles et al., Science 2004, 305, 866-869; Heinz et al., Angew. Chem. 2005, 117, 1324-1327; Angew. Chem. Int. Ed. 2005, 44, 1298-1301] of a tubulin-EpoA complex that appears to accommodate most of the published SAR data.
As discussed further below, a new study based on the above model led to the identification of the most potent, natural or designed, epothilone compounds reported to date.